A small-molecule therapeutic lead for Huntington's disease: Preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse
| Autor: | Peter Waldmeier, Jonathan H. Fox, Anne B. Young, Aleksey G. Kazantsev, Greg Lieberman, Vanita Chopra, Steven M. Hersch, David E. Housman, Wayne R. Matson, Kathryn Dorsey |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Genetically modified mouse
Huntingtin Drug Evaluation Preclinical Mice Transgenic Nerve Tissue Proteins Motor Activity Biology Blood–brain barrier Mice Huntington's disease Huntingtin Protein medicine Animals Anilides Nuclear protein Neurons Sulfonamides Multidisciplinary Neurodegeneration Nuclear Proteins Anatomy Biological Sciences medicine.disease Cell biology Biomarker (cell) Neostriatum Huntington Disease medicine.anatomical_structure Blood-Brain Barrier Female Atrophy |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:16685-16689 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0707842104 |
| Popis: | Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine expansion within huntingtin protein. The exact pathological mechanisms determining disease onset and progression remain unclear. However, aggregates of insoluble mutant huntingtin (mhtt), a hallmark of HD, are readily detected within neurons in HD brain. Although aggregated polyglutamines may not be inherently toxic, they constitute a biomarker for mutant huntingtin useful for developing therapeutics. We previously reported that the small molecule, C2-8, inhibits polyglutamine aggregation in cell culture and brain slices and rescues degeneration of photoreceptors in a Drosophila model of HD. In this study, we assessed the therapeutic potential of C2-8 in the R6/2 mouse model of HD, which has been used to provide proof-of-concept data in considering whether to advance therapies to human HD. We show that, at nontoxic doses, C2-8 penetrates the blood–brain barrier and is present in brain at a high concentration. C2-8-treated mice showed improved motor performance and reduced neuronal atrophy and had smaller huntingtin aggregates. There have been no prior drug-like, non-toxic, brain-penetrable aggregation inhibitors to arise from cell-based high-throughput screens for reducing huntingtin aggregation that is efficacious in preclinical in vivo models. C2-8 provides an essential tool to help elucidate mechanisms of neurodegeneration in HD and a therapeutic lead for further optimization and development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|